1. Eield of the Invention
This invention relates generally to ultrasonically-reflective microsphere contrast agents for ultrasonic imaging and more particularly to the quantitative detection of microspheres in biological applications.
2. Description of the Related Art
Ultrasonically-reflective microsphere contrast agents are used in medical ultrasonic imaging to enhance the image obtained by increasing the contrast of and outlining the anatomic structures being studied, for example the heart (its chambers, blood vessels, and tissue). An example of such an agent is Albunex, available from Molecular Biosystems, San Diego, Calif. Microsphere contrast agents are also used to ultrasonically assess adequacy of blood flow (i.e., perfusion) to the heart muscle (i.e., myocardium). Assessment of perfusion allows determination of the existence or risk of a myacardial infarction (i.e., a heart attack), in which the heart muscle dies because of blockage by plaque of the blood vessels supplying it.
Currently, microsphere contrast agents must be injected directly into the arteries of the heart muscle in order to be detectable with conventional ultrasonic scanners (via video intensity) and to thereby allow assessment of myacardial perfusion. Consequently, this technique is available only during cardiac surgery or catheterization. Non-invasive procedures such as peripheral intraveneous injection of the microspheres are desirable. However, dilutional effects and trapping of the larger, more reflective microspheres by the lung circulation lowers the effective microsphere concentration to such a degree that conventional ultrasonic scanners can no longer detect them in the myacardium.
Monaghan (U.S. Pat. No. 5,255,683) discloses a method of microsphere detection based on a shift in the radiofrequency (RF) spectrum of the ultrasonic myocardial echo when microspheres are present. This method is used to assess myocardial perfusion in patients. This spectral shift method does not involve the mixing of two frequencies by the microspheres with a subsequent emission of a third frequency by the microspheres. The method disclosed by Monaghan is only a qualitative detector of microsphere presence or absence. It does not allow quantitative estimation of the microsphere level in the myocardium and thus has limited use in assessing myocardial perfusion.
Shrope et al. in Ultrasonic Imaging 14(2), April 1992, investigated a method of detection based on generation by the microspheres of an RF second harmonic of the transmitted scanner frequency. As the second harmonic generated by the myocardium is of much lower magnitude, presence of the harmonic correlates with presence of the microspheres. Microsphere level in the myocardium per unit time can thus be measured and myocardial perfusion derived. The second harmonic detection method, however, requires that the microspheres have a fairly specific shell type, and will currently work only with specific agents such as SHU508 (available from the Schering Corp. in Germany).
Albert (U.S. Pat. No. 4,608,993) discloses measuring blood flow using the Doppler shift of ultrasound by blood components in a blood vessel. However, this non-invasive technique does not use microsphere contrast agents.